Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2− metastatic breast cancer

Abstract

Background

Several recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) have demonstrated significant improvements in progression-free survival (PFS); however, few have reported improvement in overall survival (OS). The surrogacy of PFS or time to progression (TTP) for OS has not been formally investigated in HR+, HER2− MBC.

Methods

A systematic literature review of RCTs in HR+, HER2− MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson’s product–moment correlation and Spearman’s rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater) on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE]).

Results

Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P=0.000; Spearman =0.650, P=0.000). These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R² of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months. Controlling the type of treatment (chemotherapy vs hormonal/targeted therapy), line of therapy (first vs subsequent), and progression measure (PFS vs TTP) led to an improved R² of 0.569 with 1 PFS/TTP month corresponding to 0.78 OS months. The STE for OS benefit was 5–6 months of incremental PFS/TTP.

Conclusion

We demonstrated a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as a surrogate for OS benefit in HR+, HER2− MBC.

Keywords:

• breast cancer
• overall survival
• progression-free survival
• time to progression
• correlation analysis
• surrogate endpoint

Supplementary materials

Table S1 Search strategy for MEDLINE

Table S2 Search strategy for Embase

Table S3 Search strategy for Cochrane Library

Acknowledgments

Part of this article was presented at the 2017 European Society for Medical Oncology as a poster presentation with interim findings. The poster’s abstract was published in the Annals of Oncology (2017) 28 (suppl_5): v74–v108. 10.1093/annonc/mdx365. We thank Jaclyn Hearnden for her medical writing contributions and assistance in preparing the article. This study was sponsored by Novartis.

Author contributions

Anna Forsythe and Gabriel Tremblay made substantial contributions to the conception and design, analyzed and interpreted the data, and helped to draft the article. David Chandiwana, Janina Barth, Marroon Thabane, and Johan Baeck contributed to the conception and development of this study and evaluation and interpretation of the data. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.

Disclosure

David Chandiwana, Janina Barth, Marroon Thabane, and Johan Baeck are employees of Novartis. The authors report no other conflicts of interest in this work.